Prognostic Value of Serum NPY Hypermethylation in Neoadjuvant Chemoradiotherapy for Rectal Cancer: Secondary Analysis of a Randomized Trial

Objectives: Long-term prevention of metastatic disease remains a challenge in locally advanced rectal cancer, and robust pretreatment prognostic factors for metastatic progression are lacking. We hypothesized that detecting circulating tumor-specific DNA (ctDNA) based on hypermethylation of the neuropeptide Y gene (meth-ctDNA) could be a prognostic marker in the neoadjuvant setting; we examined this in a secondary, explorative analysis of a prospective trial. Materials and Methods: Serum samples were prospectively collected in a phase III trial for locally advanced rectal cancer. Positivity for and fractional abundance of meth-ctDNA in baseline samples were estimated. Overall survival (OS) and the rate of distant metastases were compared between meth-ctDNA positive and negative patients; other prognostic factors were controlled for in multivariate Cox regression. Importance of quantitative load was examined by considering the fractional abundance of meth-ctDNA relative to total circulating DNA. Results: Baseline serum samples were available for 146 patients. In total, 30 patients had presence of meth-ctDNA, with no correlation with cT (P=0.8) or cN (P=0.6) stages. Median follow-up was 10.6 years for OS and 5.1 years for freedom from distant metastases. Patients with meth-ctDNA had significantly worse 5-year OS (47% vs. 69%), even when controlling for other prognostic factors (hazard ratio=2.08; 95% confidence interval, 1.23-1.51). This seemed mainly driven by disparity in the rate of distant metastases (55% vs. 72% at 5 y, P=0.01); hazard ratio=2.20 (95% confidence interval, 1.19-4.07, P=0.01) in multivariate analysis. Increased quantitative load was highly significant for worse outcomes. Conclusions: Meth-ctDNA could be a potential prognostic marker in the neoadjuvant setting and may, if validated, identify patients at increased risk of distant metastases

Late-type galaxies observed with SAURON. Two-dimensional stellar and emission-line kinematics of 18 spirals

We present the stellar and gas kinematics of a sample of 18 nearby late-type spiral galaxies (Hubble types ranging from Sb to Sd), observed with the integral-field spectrograph SAURON at the 4.2-m William Herschel Telescope. SAURON covers the spectral range 4800-5380 A, allowing us to measure the Hbeta, Fe, Mgb absorption features and the emission in the Hbeta line and the [OIII], and [NI] doublets over a 33x41 arcsec field of view. The maps cover the nuclear region of these late-type galaxies and in all cases include the entire bulge. In many cases the stellar kinematics suggests the presence of a cold inner region, as visible from a central drop in the stellar velocity dispersion. The ionised gas is almost ubiquitous and behaves in a complicated fashion: the gas velocity fields often display more features than the stellar ones, including wiggles in the zero-velocity lines, irregular distributions, ring-like structures. The line ratio [OIII]/Hbeta often takes on low values over most of the field, probably indicating a wide-spread star formation.Comment: 34 pages, 24 figures. Accepted for publication in MNRAS. A version with full resolution figures is available at http://www.strw.leidenuniv.nl/sauron/papers/ganda2005_late_types.pd

A comparison of hospital readmission rates between two general physicians with different outpatient review practices

BACKGROUND: There has been a relentless increase in emergency medical admissions in the UK over recent years. Many of these patients suffer with chronic conditions requiring continuing medical attention. We wished to determine whether conventional outpatient clinic follow up after discharge has any impact on the rate of readmission to hospital. METHODS: Two consultant general physicians with the same patient case-mix but markedly different outpatient follow-up practice were chosen. Of 1203 patients discharged, one consultant saw twice as many patients in the follow-up clinic than the other (Dr A 9.8% v Dr B 19.6%). The readmission rate in the twelve months following discharge was compared in a retrospective analysis of hospital activity data. Due to the specialisation of the admitting system, patients mainly had cardiovascular or cerebrovascular disease or had taken an overdose. Few had respiratory or infectious diseases. Outpatient follow-up was focussed on patients with cardiac disease. RESULTS: Risk of readmission increased significantly with age and length of stay of the original episode and was less for digestive system and musculo-skeletal disorders. 28.7% of patients discharged by Dr A and 31.5 % of those discharged by Dr B were readmitted at least once. Relative readmission risk was not significantly different between the consultants and there was no difference in the length of stay of readmissions. CONCLUSIONS: Increasing the proportion of patients with this age- and case-mix who are followed up in a hospital general medical outpatient clinic is unlikely to reduce the demand for acute hospital beds

Survey of the needs of patients with spinal cord injury: impact and priority for improvement in hand function in tetraplegics\ud

Objective: To investigate the impact of upper extremity deficit in subjects with tetraplegia.\ud \ud Setting: The United Kingdom and The Netherlands.\ud \ud Study design: Survey among the members of the Dutch and UK Spinal Cord Injury (SCI) Associations.\ud \ud Main outcome parameter: Indication of expected improvement in quality of life (QOL) on a 5-point scale in relation to improvement in hand function and seven other SCI-related impairments.\ud \ud Results: In all, 565 subjects with tetraplegia returned the questionnaire (overall response of 42%). Results in the Dutch and the UK group were comparable. A total of 77% of the tetraplegics expected an important or very important improvement in QOL if their hand function improved. This is comparable to their expectations with regard to improvement in bladder and bowel function. All other items were scored lower.\ud \ud Conclusion: This is the first study in which the impact of upper extremity impairment has been assessed in a large sample of tetraplegic subjects and compared to other SCI-related impairments that have a major impact on the life of subjects with SCI. The present study indicates a high impact as well as a high priority for improvement in hand function in tetraplegics.\ud \u

Surprising dissimilarities in a newly formed pair of 'identical twin' stars

The mass and chemical composition of a star are the primary determinants of its basic physical properties--radius, temperature, luminosity--and how those properties evolve with time. Thus, two stars born at the same time, from the same natal material, and with the same mass are 'identical twins,' and as such might be expected to possess identical physical attributes. We have discovered in the Orion Nebula a pair of stellar twins in a newborn binary star system. Each star in the binary has a mass of 0.41 +/- 0.01 solar masses, identical to within 2 percent. Here we report that these twin stars have surface temperatures that differ by ~300K (~10%), and luminosities that differ by ~50%, both at high confidence level. Preliminary results indicate that the stars' radii also differ, by 5-10%. These surprising dissimilarities suggest that one of the twins may have been delayed by several hundred thousand years in its formation relative to its sibling. Such a delay could only have been detected in a very young, definitively equal-mass binary system3 such as that reported here. Our findings reveal cosmic limits on the age synchronisation of young binary stars, often used as tests for the age calibrations of star-formation models.Comment: Published in Nature, 19 June 200

A new approach to bad news effects on volatilit y: the multiple-sign-volume sensitive regime EGARCH model (MSV-EGARCH)

In this paper, using daily data for six major international stock market indexes and a modified EGARCH specification, the links between stock market returns, volatility and trading volume are investigated in a new nonlinear conditional variance framework with multiple regimes and volume eff ects. Volatility forecast comparisons, using the Harvey-Newbold test for multiple forecasts encompassing, seem to demonstrate that the MSV- EGARCH complex threshold structure is able to correctly fit GARCH- type dynamics of the series under study and dominates competing standard asymmetric models in several of the considered stock indexes.info:eu-repo/semantics/publishedVersio

Serum microRNA array analysis identifies miR-140-3p, miR-33b-3p and miR-671-3p as potential osteoarthritis biomarkers involved in metabolic processes.

Background: MicroRNAs (miRNAs) in circulation have emerged as promising biomarkers. In this study, we aimed to identify a circulating miRNA signature for osteoarthritis (OA) patients and in combination with bioinformatics analysis to evaluate the utility of selected differentially expressed miRNAs in the serum as potential OA biomarkers. Methods: Serum samples were collected from 12 primary OA patients, and 12 healthy individuals were screened using the Agilent Human miRNA Microarray platform interrogating 2549 miRNAs. Receiver Operating Characteristic (ROC) curves were constructed to evaluate the diagnostic performance of the deregulated miRNAs. Expression levels of selected miRNAs were validated by quantitative real-time PCR (qRT-PCR) in all serum and in articular cartilage samples from OA patients (n = 12) and healthy individuals (n = 7). Bioinformatics analysis was used to investigate the involved pathways and target genes for the above miRNAs. Results: We identified 279 differentially expressed miRNAs in the serum of OA patients compared to controls. Two hundred and five miRNAs (73.5%) were upregulated and 74 (26.5%) downregulated. ROC analysis revealed that 77 miRNAs had area under the curve (AUC) > 0.8 and p < 0.05. Bioinformatics analysis in the 77 miRNAs revealed that their target genes were involved in multiple signaling pathways associated with OA, among which FoxO, mTOR, Wnt, pI3K/akt, TGF-β signaling pathways, ECM-receptor interaction, and fatty acid biosynthesis. qRT-PCR validation in seven selected out of the 77 miRNAs revealed 3 significantly downregulated miRNAs (hsa-miR-33b-3p, hsa-miR-671-3p, and hsa-miR-140-3p) in the serum of OA patients, which were in silico predicted to be enriched in pathways involved in metabolic processes. Target-gene analysis of hsa-miR-140-3p, hsa-miR-33b-3p, and hsa-miR-671-3p revealed that InsR and IGFR1 were common targets of all three miRNAs, highlighting their involvement in regulation of metabolic processes that contribute to OA pathology. Hsa-miR-140-3p and hsa-miR-671-3p expression levels were consistently downregulated in articular cartilage of OA patients compared to healthy individuals. Conclusions: A serum miRNA signature was established for the first time using high density resolution miR-arrays in OA patients. We identified a three-miRNA signature, hsa-miR-140-3p, hsa-miR-671-3p, and hsa-miR-33b-3p, in the serum of OA patients, predicted to regulate metabolic processes, which could serve as a potential biomarker for the evaluation of OA risk and progression.Peer reviewedFinal Published versio

Minding impacting events in a model of stochastic variance

We introduce a generalisation of the well-known ARCH process, widely used for generating uncorrelated stochastic time series with long-term non-Gaussian distributions and long-lasting correlations in the (instantaneous) standard deviation exhibiting a clustering profile. Specifically, inspired by the fact that in a variety of systems impacting events are hardly forgot, we split the process into two different regimes: a first one for regular periods where the average volatility of the fluctuations within a certain period of time is below a certain threshold and another one when the local standard deviation outnumbers it. In the former situation we use standard rules for heteroscedastic processes whereas in the latter case the system starts recalling past values that surpassed the threshold. Our results show that for appropriate parameter values the model is able to provide fat tailed probability density functions and strong persistence of the instantaneous variance characterised by large values of the Hurst exponent is greater than 0.8, which are ubiquitous features in complex systems.Comment: 18 pages, 5 figures, 1 table. To published in PLoS on